Pharmacokinetic characterization of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone, a novel 11β-hydroxysteroid dehydrogenase type 1 inhibitor in rats

• Published in: Archives of pharmacal research Vol. 39; no. 4; pp. 492 - 498
• Main Authors: Zheng, Zhi, Seo, Hyewon, Kwak, Hyun Jung, Kim, Ki Young, Ahn, Jin Hee, Bae, Myung Ae, Song, Jin Sook
• Format: Journal Article
• Language: English
• Published: Seoul Pharmaceutical Society of Korea 01.04.2016; 대한약학회
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; Administration, Oral; Animals; bioavailability; Biological Availability; blood proteins; Blood Proteins - metabolism; Caco-2 Cells; Cell Membrane Permeability; Cyclic S-Oxides - administration & dosage; Cyclic S-Oxides - chemistry; Cyclic S-Oxides - pharmacokinetics; Cyclic S-Oxides - pharmacology; Dogs; Drug Evaluation, Preclinical; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Half-Life; human cell lines; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Injections, Intravenous; intravenous injection; liver; Male; Medicine; Mice; Microsomes, Liver - metabolism; Molecular Structure; noninsulin-dependent diabetes mellitus; obesity; oral administration; permeability; pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Protein Binding; rats; Rats, Sprague-Dawley; Research Article; Solubility; Thiazines - administration & dosage; Thiazines - chemistry; Thiazines - pharmacokinetics; Thiazines - pharmacology; Tissue Distribution; 약학; 11β-hydroxysteroid dehydrogenase type 1; Metabolic stability; Plasma protein binding; Caco-2 cell permeability; Pharmacokinetics
• ISSN: 0253-6269; 1976-3786; 1976-3786
• DOI: 10.1007/s12272-015-0702-8

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is associated with metabolic syndromes such as type 2 diabetes mellitus and obesity. A new 11β-HSD1 inhibitor known as 2-(3-benzoyl)-4-hydroxy-1, 1-dioxo-2H-1, 2-benzothiazine-2-yl-1-phenylethanone (KR-66344) is being developed as a therapeutic agent for these metabolic diseases. The purpose of this study was to characterize the pharmacokinetics of KR-66344 to support further preclinical development. KR-66344 showed high liver microsomal stability with T 1/2 values >3 h and high permeability with apparent permeability coefficients of 15.2–24.2 × 10 −6  cm/s in Caco-2 cell monolayers. KR-66344 was also strongly bound to plasma proteins (>98 %). After intravenous dosing, KR-66344 exhibited low systemic clearance (0.27–0.37 L/h/kg) and a low to moderate volume of distribution at steady state (0.79–0.8 L/kg). The bioavailability and terminal half-lives of KR-66344 following oral administration were 25 % and 1.7–3.3 h, respectively. In addition, KR-66344 showed dose-independent pharmacokinetics at 0.5–10 mg/kg in intravenous and oral pharmacokinetic studies.